GeNeViSTA

1 Abstract

Coffin-Siris syndrome (CSS) is classically characterized by aplasia/hypoplasia of the distal phalanx or nail of the fifth digit, coarse facial features and moderate to severe developmental delay. CSS is a genetically heterogeneous disorder with clinical variability. Recently, mutations in five genes which encode for subunits of the ATP dependent chromatin-remodeling complex- switch/sucrose non-fermenting (SWI/SNF): SMARCB1, SMARCA4, SMARCE1, ARID1A and ARID1B, have been found to be responsible for the disorder. The CSS phenotypes and the SWI/SNF complex are discussed in this paper.

2 Introduction

Coffin-Siris syndrome (CSS) also known as “Fifth digit syndrome” (OMIM#135900) is a genetic disorder, classically characterized by aplasia/hypoplasia of the distal phalanx or nail of the fifth digit, coarse facial features and moderate to severe developmental/cognitive delay. Other findings commonly include failure to thrive, feeding difficulties, frequent infections, short stature, hypertrichosis, sparse scalp hair, ophthalmologic abnormalities, microcephaly, brain malformations, speech delay and hearing loss, etc. (Figs. 1, 2, 3, 4). It was first described by Coffin and Siris in 1970 in 3 unrelated girls with severe mental retardation, absent nails and hypoplastic distal phalanges of fifth fingers (Coffin & Siris, 1970). CSS is inherited in an autosomal dominant manner. Mutations in five genes encoding subunits of the ATP dependent chromatin-remodeling complex- switch/sucrose non-fermenting (SWI/SNF): SMARCB1, SMARCA4, SMARCE1, ARID1A, and ARID1B have been found to be responsible for the disorder and have been identified by whole exome sequencing and pathway-based genetic testing (Fig. 5). Further SOX11 mutations have been recently discovered in CSS patients with a mild phenotype. SOX11 is the downstream transcriptional factor of the PAX6-BAF complex.

3 CSS: A Genetically Heterogeneous Disorder

CSS has a distinct clinical phenotype. Clinical criteria of CSS include three major findings and one of each of the three minor findings. The major findings are fifth digit nail/distal phalanx hypoplasia/aplasia, developmental/cognitive delay and coarse facial features with bushy eyebrows, thick lips, broad nasal bridge with bulbous nasal tip. Minor findings include- 1) ectodermal findings like hirsutism, sparse scalp hair, dental anomalies; 2) constitutional findings like intrauterine growth retardation (IUGR), short stature, microcephaly, failure to thrive, frequent infections; 3) organ related findings like cardiac anomalies, feeding difficulties, genitourinary/renal anomalies, gastrointestinal anomalies and brain/cranial malformations.

Because molecular genetic testing has identified causative pathogenic variants in several individuals with coarse facial features and intellectual disability that overlap with classic CSS but with little or no fifth digit hypoplasia/aplasia, evaluation of individuals with a broader phenotype is required to determine the frequency of this finding in individuals with molecularly confirmed CSS. Newer diagnostic criteria are likely to evolve to include both clinical features and molecular findings to evaluate a broader phenotype for CSS. For example ARID1B variants have been found in persons with intellectual disability, some without distal digital or fifth finger hypoplasia/aplasia [Halgren et al., 2012; Santen et al., 2012].

4 Genotype-Phenotype Correlation

Genotype-phenotype correlations in CSS have not been clearly defined. Pathogenic variants in ARIDB1 have been identified in individuals with mild CSS and/or apparently isolated intellectual disability by exome sequencing (Hoyer et al., 2012). These individuals have many features of CSS like developmental delay, hearing loss, seizures and dysmorphic facial features but only a subset has fifth digit anomalies. In addition to classic features, individuals with SMARCB1 mutations are associated with severe neurodevelopmental abnormalities including CNS structural abnormalities, severe intellectual disability, seizures, scoliosis and speech delay; expressive language being affected predominantly. Especially, those with a recurrent mutation “p.Lys364del” presented strikingly similar phenotypes including characteristic coarse facial features. Patients with SMARCA4 mutations have less coarse craniofacial appearances and behavioral abnormalities. SMARCE1 mutations have a wide spectrum of manifestations from moderate to severe intellectual disability. Patients with ARID1A mutations have a wide spectrum of manifestations from mild to severe intellectual disability and serious internal complications due to cardiac anomalies, feeding difficulties, genitourinary/renal anomalies, gastrointestinal anomalies and brain/cranial malformations that could result in early death.

Mutation in genes involved in CSS also causes cancer. ARID1B truncating mutations (and one small in-frame deletion) were identified in breast cancer tissue. Inactivating mutations of ARID1A are a common feature of gastric cancer and truncating somatic mutations of endometriosis-associated ovarian clear cell and endometrioid carcinoma. Recently, missense mutations of SMARCA4 were identified in medulloblastoma and SMARCB1 in meningiomas. Truncating as well as missense mutations in SMARCB1 in the germline are associated with Schwannomatosis, a tumor suppressor syndrome. SMARCE1 mutations have not been unequivocally linked to tumor formation, but two truncating mutations which are thought to lead to haploinsufficiency were reported in the breast cancer tissue (Santen et al., 2012).

5 SWI/SNF Complex and its Function

The DNA in human chromosomes is packed in the cell nucleus in the form of nucleosomes, which are formed by ~147 bp of DNA wrapped around histone proteins. Nucleosomes are assembled into condensed chromatin which inhibits access to DNA for cellular proteins that drive chromatin-based processes, including transcription and DNA repair. An important step in the regulation of these nuclear processes is the modulation of chromatin structure. It can be achieved by two mechanisms either by involving the modification of residues in the histone tails or by the activity of ATP-dependent chromatin remodeling complexes (Santen et al., 2012). SWI/SNF (Switch/Sucrose Non-Fermentable) are the chromatin remodeling complexes present in human cells and play an important role in transcription, cell differentiation, DNA repair, and tumor suppression.

The SWI/SNF complex was first discovered in the yeast, Saccharomyces cerevisiae and is named after yeast mating types switching (SWI) and sucrose non-fermenting (SNF). The SWI/SNF complex in yeast contains the ATPase Swi2/Snf2p, two actin-related proteins (Arp7p and Arp9) and other subunits involved in DNA and protein-protein interactions which causes alteration of nucleosome structure in an ATP-dependent manner. RSC (Remodeling the Structure of Chromatin), a closely related complex, was also identified in yeast. This complex is composed of 17 subunits and shows similarities to the SWI/SNF complex. The structures of the SWI/SNF and RSC complexes are highly conserved, but their compositions are not identical, reflecting an increasing complexity of chromatin through evolution. SWI/SNF and RSC complexes in higher eukaryotes maintain core components to maintain overall shape and remodeling activity and also substitute or add on other components with more specialized or tissue-specific domains. As in yeast, humans contain two distinct remodeling complexes homologous to SWI/SNF and RSC, respectively. These two complexes are called BAF (BRG1 Associated Factors) and PBAF (Polybromo-associated BAF) (Table 1).